Abstract: Diabetes mellitus (DM) is a common metabolic disease in the middle-aged and older population, which is associated with cognitive decline and an increased risk of developing dementia in the elderly. Given the growing size of the aging population and increased prevalence of DM, development of specific interventions to maintain cognitive integrity by counteracting DM induced pathophysiological processes is of major clinical importance. Clinical trials show that the achievement of improved glycemic control may not prevent progression of cognitive impairment. The underlying cause of DM-induced cognitive deficits remains unknown. Exosomes are nanovesicles with a size of 40 to 120 nm in diameter and mediate intercellular communication by transferring proteins, lipids, and genomic materials including mRNAs and microRNAs (miRNAs) between source and target cells. Our preliminary data demonstrated aged-DM rats exhibit substantial cognitive impairment, which is associated with dysfunction of cerebral endothelial cells and neural stem cells. We also found that exosomes derived from dysfunctional cerebral endothelial cells induced by DM communicated with and damaged neural stem cells. More importantly, administration of exosomes isolated from cerebral endothelial cells of healthy young adult brain to aged-DM rats effectively improved cognitive function and minimize DM-induced dysfunction of cerebral endothelial cells and neural stem cells. In this application, we therefore, propose to develop the endothelial exosomes as a mechanism-based therapy for DM-induced cognitive decline in aged population. Our hypotheses are: 1) The cerebral endothelial exosome (CEE) treatment reduces cognitive deficits in the aged-DM rat, 2) The CEE treatment improves cerebral vascular patency and integrity, and promotes neurogenesis and oligodendrogenesis in the aged-DM rat, and 3) Engineered exosomes carrying elevated miR-1 and -146a have enhanced effects on cerebral vascular function, neurogenesis and oligodendrogenesis as well as cognitive function. Aim 1 is to investigate whether the CEE derived from young adult rats improve cognitive function in the aged-DM rat, when the CEE is administered at an early (2 months) or advanced (4 months) stage of DM in aged male and female rats. Aim 2 is to investigate whether the CEE treatment improves cerebral vascular function and enhances neurogenesis and oligodendrogenesis in the aged-DM rat. Cerebral vascular patency and integrity, neurogenesis and oligodendrogenesis will be measured. Aim 3 is to investigate whether treatment of the aged-DM rat with tailored endothelial exosomes carrying elevated miR-1 and miR146a further enhances vascular function, neurogenesis and oligodendrogenesis as well as cognitive function. We will generate the tailored CEE and then administer the tailored CEE to aged-DM rats. These studies are innovative and highly clinically relevant.